Early diagnosis of diseases involving rare cells in blood (such as metastatic cancer or low-level bacteremia) and accurate monitoring of certain genetic conditions (such as sickle cell anemia) require rapid and accurate separation, sorting, and direction of target cell types toward a sensor surface. In that regard, cellular manipulation, separation, and sorting are increasingly finding application potential within various bioassays in the context of cancer diagnosis (Dittrich et al., 2006, Nat Rev Drug Discovery 5:210-218), pathogen detection (Beyor et al., 2008, Blamed Microdevices 10:909-917), and genomic testing (Kamei et al. 2005, Biomed Microdevices 7:147-152; Cheong et al., 2008, Lab Chip 8:810-813).
A variety of contactless micromanipulation methods exist, including optical tweezers (Ashkin et al., 1987, Nature 330:769-771; Chian et al., 2005, Nature 436:370-372), dielectrophoresis (DEP) (Hughes, 2002, Electrophoresis 23:2569-2582), magnetic bead-based separators (Lee et al., 2001, Appl Phys Lett 79:3308-3310; Yan et al., 2004, Phys Rev E 70:011905), and deterministic hydrodynamics (Davis et al., 2006, Proc Natl Acad Sci USA 103:14779-14784). However, many existing methods have been unable to reliably achieve fast speed, high throughput and resolution, simultaneously with low costs (Dufresne et al., 1998, Rev Sci Instrum 69:1974-1977; Kremser et al., 2004, Electrophoresis 25:2282-2291; Cabrera et al., 2001, Electrophoresis 22:355-362). Optical tweezers offer high resolution and sensitivity for manipulating single cells, although such manipulation may cause sample heating (Liu et al., 1995, Biophys J 68:2137-2144), and is typically limited to a very small area (Ashkin et al., 1987, Science 235:1517-1520). Holographic schemes have recently extended the reach of optical tweezers to several tens of cells simultaneously (Applegate et al., 2004, Optical Express 12:4390-4398), although the overall throughput remains quite low.
Schemes based on electric fields, such as DEP, offer the potential to realize integrated, cost effective devices for the simultaneous manipulation of multiple cells. Nevertheless, their performance depends sensitively on the electrical properties of the specific liquid medium, the particle shape, and its effective dielectric constant (Pethig et al., 1997, Trends Biotechnol 15:426-432). DEP device operating regimes and the working ionic medium need to be carefully optimized for each different cell type so as to reach a workable compromise between the need to reduce heating (Menachery et al., 2005, NanoBiotechnology 152:145149; Muller, et al., 2003, IEEE Eng Biol Med Mag 22:51-61) and minimize cell polarization (Sebastian et al., 2006, J Micromech Microeng 16:1769-1777). Using functionalized magnetic beads to separate target molecules and cells overcomes these challenges through the use of magnetic fields instead of electric. However, the downside of this technique is the lengthy incubation times and wash cycles, and the difficulty of removing the label post priori (Gijs 2004, Microfluidics Nanofluidics 1:22-40). The deterministic hydrodynamics approach, as demonstrated by Davis et al. (Davis et al., 2006, Proc Natl Acad Sci USA 103:1477914784), is capable of achieving high resolution of separation without the use of any electromagnetic fields. However, high throughput with this device requires high-resolution lithography on a large area, keeping the cost per device high.
Most common applications of ferrofluids in biomedicine involve highly dilute colloidal suspensions of magnetic nanoparticles. Their widest commercial use is as MRI contrast agents (Kim et al., 2005, J Magn Magn Mater 289:328-330). When properly coated with targeting antibodies, they can also be used in hyperthermia therapy for cancer or as sensors to detect pathogens (Scherer et al., 2005, Brazilian J Phys 45:718-727).
While these advances in the use of ferrofluids provide many opportunities in medicine and diagnostics, there remains a need in the art for a microfluidic platform that uses biocompatible ferrofluids for the controlled manipulation and rapid separation of both microparticles and live cells.